金钱草治疗胆囊相关疾病作用机制的网络药理学研究
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摘要
目的:采用网络药理学方法探究金钱草治疗胆囊相关疾病的作用机制。方法:通过中药系统药理学数据库与分析平台(TCMSP),以"类药五原则"和"口服吸收利用度(OB)>30%"为标准筛选金钱草活性成分,预测相关靶点,并利用Cytoscape 3.2.1软件构建活性成分-靶点网络;在数据库TTD、OMIM、PharmGKB、DrugBank和GAD中,以"胆石症""胆结石""胆囊炎"和"胆管炎"为关键词预测相关靶点,构建疾病-靶点网络,并与活性成分作用靶点融合,获得治疗靶点,使用数据库DAVID对靶点进行通路富集分析,以靶点与活性成分进行分子对接,以此筛选出金钱草发挥治疗作用的主要成分。结果:筛选获得金钱草中具有类药性、口服吸收较好的27种成分;通过网络构建、融合得到金钱草作用靶点33个,通路富集分析得到相关通路7条,主要涉及癌症通路、ABC转运体通路等;金钱草活性成分中对接得分排序前4位的分别是山柰酚、金合欢素、橙皮素和异鼠李素,主要作用于ABCC3、ABCB1、ABCC2、ABCB4靶点。结论:金钱草主要通过ABC转运体通路发挥治疗胆囊相关疾病的作用。
OBJECTIVE:To explore the mechanism of Lysimachia christinae in the treatment of cholecyst related diseases by network pharmacology. METHODS:The active ingredients of L. christinae were screened through TCMSP database with"Lipinski rule"and"Oral bioavailability >30% "rules,and their related targets were predicated correspondingly,then compound-target network were constructed by Cytoscape 3.2.1 software. Disease related targets were predicted by searching TTD database,OMIM database, PharmGKB database, DrugBank database and GAD database with "cholelithiasis""gallstones""cholecystitis" and"cholangitis"as keywords. Then,the network of disease-target was constructed and merged with active ingredient target to obtain therapeutic target. After pathway enrichment analysis of therapeutic target were performed by utilizing the DAVID database,molecular docking between target and active ingredient was also conducted in order to screen the main active ingredients of L.christinae. RESULTS:Twenty-seven active ingredients with good oral absorption and drug-like properties were screened from L.christinae. Thirty-three targets were attained after constructing and merging the network. Seven pathways,mainly related to cancer pathway and ABC transporter pathway were achieved. Top 4 active ingredients of L. christinae in the list of docking score were kaempferin,acacia,hesperetin and isorhamnetin,which acted on ABCC3,ABCB1,ABCC2,ABCB4 target. CONCLUSIONS:L.christinae treat cholecyst related diseases through ABC transporter pathway.
OBJECTIVE:To explore the mechanism of Lysimachia christinae in the treatment of cholecyst related diseases by network pharmacology. METHODS:The active ingredients of L. christinae were screened through TCMSP database with"Lipinski rule"and"Oral bioavailability >30% "rules,and their related targets were predicated correspondingly,then compound-target network were constructed by Cytoscape 3.2.1 software. Disease related targets were predicted by searching TTD database,OMIM database, PharmGKB database, DrugBank database and GAD database with "cholelithiasis""gallstones""cholecystitis" and"cholangitis"as keywords. Then,the network of disease-target was constructed and merged with active ingredient target to obtain therapeutic target. After pathway enrichment analysis of therapeutic target were performed by utilizing the DAVID database,molecular docking between target and active ingredient was also conducted in order to screen the main active ingredients of L.christinae. RESULTS:Twenty-seven active ingredients with good oral absorption and drug-like properties were screened from L.christinae. Thirty-three targets were attained after constructing and merging the network. Seven pathways,mainly related to cancer pathway and ABC transporter pathway were achieved. Top 4 active ingredients of L. christinae in the list of docking score were kaempferin,acacia,hesperetin and isorhamnetin,which acted on ABCC3,ABCB1,ABCC2,ABCB4 target. CONCLUSIONS:L.christinae treat cholecyst related diseases through ABC transporter pathway.
引文
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[2]国家药典委员会.中华人民共和国药典:一部[S].2015年版.北京:中国医药科技出版社,2015:184.
[3]马思佳,张文静,盛佳威,等.基于中医传承辅助系统的治疗胆结石组方规律分析[J].河北中医药学报,2018,33(1):36-39,59.
[4]GOH KI,CUSICK ME,VALLE D,et al.The human disease network[J].Proc Natl Acad Sci U S A,2007,104(21):8685-8690.
[5]LI S,ZHANG B.Traditional Chinese medicine network pharmacology:theory,methodology and application[J].Chinese Journal of Natural Medicines,2013,11(2):110-120.
[6]RU J,LI P,WANG J,et al.TCMSP:a database of systems pharmacology for drug discovery from herbal medicines[J].J Cheminform,2014.DOI:10.1186/1758-2946-6-13.
[7]MA X,LV B,LI P,et al.Identification of“multiple components-multiple targets-multiple pathways”associated with Naoxintong capsule in the treatment of heart diseases using UPLC/Q-TOF-MS and network pharmacology[J].Evidence-Based Complementray and Alternative Medicine,2016.DOI:10.1155/2016/9468087.
[8]GFELLER D,GROSDIDIER A,WIRTH M,et al.SwissTargetPrediction:a web server for target prediction of bioactive small molecules[J].Nucleic Acids Research,2014,42(Web Server issue):32-38.
[9]SHANNON P,MARKIEL A,OZIER O,et al.Cytoscape:a software environment for integrated models of biomolecular interaction networks[J].Genome Research,2003,13(11):2498-2504.
[10]LI YH,YU CY,LI XX,et al.Therapeutic target database update 2018:enriched resource for facilitating bench-toclinic research of targeted therapeutics[J].Nucleic Acids Research,2017,46(D1):D1121-D1127.
[11]HAMOSH A,SCOTT AF,AMBERGER J,et al.Online Mendelian Inheritance in Man(OMIM),a knowledgebase of human genes and genetic disorders[J].Nucleic Acids Research,2005,33(1):514-517.
[12]BARBARINO JM,WHIRL-CARRILLO M,ALTMANRB,et al.PharmGKB:a worldwide resource for pharmacogenomic information[J].Wiley Interdiscip Rev Syst Biol&Med,2018,10(4):e1417.
[13]WISHART DS,FEUNANG YD,GUO AC,et al.DrugBank 5.0:a major update to the DrugBank database for2018[J].Nucleic Acids Research,2017,46(D1):D1074-D1082.
[14]BECKER KG,BARNES KC,BRIGHT TJ,et al.The genetic association database[J].Nature Genetics,2004,36(5):431-432.
[15]PI?ERO J,BRAVO A,QUERALT-ROSINACH N,et al.DisGeNET:a comprehensive platform integrating information on human disease-associated genes and variants[J].Nucleic Acids Research,2017,45(D1):D833-D839.
[16]任青措,余羊羊,切尼项毛,等.藏药沙棘总黄酮防治慢性支气管炎的网络药理学研究[J].中国药房,2018,29(22):3119-3124.
[17]宗阳,孙明明,乐音子,等.基于网络药理学探讨白术-枳实药对治疗慢性传输型便秘的作用机制[J].中国药房,2018,29(13):1798-1802.
[18]王萍,沈玉华,谢安建,等.金钱草提取液对尿液中草酸钙晶体生长的影响[J].安徽大学学报,2006,30(1):80-84.
[19]张雅媛,马世平.金钱草对食饵性胆色素结石的防治作用[J].中药药理与临床,2004,20(2):21-22.
[20]杨金辉.金钱草粗多糖利尿排石作用机理初探[D].成都:成都中医药大学,2013.
[21]PUGLIELLI L,AMIGO L,ARRESE M,et al.Protective role of biliary cholesterol and phospholipid lamellae against bile acid-induced cell damage[J].Gastroenterology,1994,107(1):244-254.
[22]OUDE ELFERINK RP,PAULUSMA CC.Function and pathophysiological importance of ABCB4(MDR3 P-glycoprotein)[J].Pflugers Arch,2007,453(5):601-610.
[23]JACQUEMIN E,DE VREE JM,CRESTEIL D,et al.The wide spectrum of multidrug resistance 3 deficiency:from neonatal cholestasis to cirrhosis of adulthood[J].Gastroenterology,2001,120(6):1448-1458.
[24]BLIEK AM,BAAS F,LANGE TT,et al.The human mdr3gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver[J].Embo Journal,1987,6(11):3325-3331.
[25]KHABOU B,DURAND-SCHNEIDER AM,DELAUNAYJL,et al.Comparison of in silico prediction and experimental assessment of ABCB4 variants identified in patients with biliary diseases[J].Int J Biochem Cell Biol,2017.DOI:10.1016/j.biocel.2017.05.028.
[26]DE VREE JM,JACQUEMIN E,STURM E,et al.Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis[J].Proc Natl Acad Sci U S A,1998,95(1):282-287.
[27]SCHATZ SB,JüNGST C,KEITEL-ANSELMO V,et al.Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset[J].Hepatology Communications,2018,2(5):504-514.
[28]NAKKEN KE,NYG?RD S,HAALAND T,et al.Multiple inflammatory,tissue remodelling and fibrosis genes are differentially transcribed in the livers of Abcb4(-/-)mice harbouring chronic cholangitis[J].Scand J Gastroenterol,2007,42(10):1245-1255.